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  • Estrogen related receptors ERRs are orphan nuclear receptors


    Estrogen-related receptors (ERRs) are orphan nuclear receptors and have three members including ERRα, ERRβ, and ERRγ (Yasumoto et al., 2007). Though they are termed as ERRs due to the sequence homology with estrogen receptors, they don’t need to bind estrogens to exert action. Generally, ERRs bind to estrogen-related response elements and modulate gene transcription with no activation by estrogens (Takeda et al., 2009). In streptozotocin-induced diabetes, ERRα was upregulated in heart, suggesting an association with diabetes-related cardiac injury (Huss et al., 2015). In breast cancer, ERRα could bind to specific DNA regions to modify the expressions of genes associated with cancer development (Deblois et al., 2010). ERRα and ERRγ also can form a complex with PGC-1α to modulate energy homeostasis (Canto et al., 2010). Among three ERR members, ERRγ is highly expressed in heart, kidney, and skeletal muscle (Yasumoto et al., 2007, Teng et al., 2011). Systemic deletion of ERRγ led to perinatal lethality in mice possibly because of the impaired energy metabolism in heart (Alaynick et al., 2007). Analysis from adult human tissues demonstrated the high expression of ERRγ in human kidneys (Hentschke and Borgmeyer, 2003). However, the role of ERRγ in kidney injury, particularly in podocyte injury is still unknown.
    Materials and methods
    Discussion Podocytes are highly differentiated glomerular epithelial long queue and play critical roles in maintaining the integrity of glomerular basement membrane. Impairment of the structure and function of podocytes contributes to the occurrence of proteinuria, as well as the progression of kidney diseases (Schiffer et al., 2001, Saurus et al., 2015). Though a number of studies have been performed to explore the pathological mechanisms contributing to the podocyte injury, the pathogenesis of podocyte injury is still uncertain. ERRγ have been shown to be associated with diabetes, cancer, and energy metabolism. However, the role of ERRγ in podocyte apoptosis is still unknown. In the present study, we investigated the involment of ERRγ in podocyte apoptosis with or without PAN treatment. Following PAN administration, we found a striking decrease of ERRγ at both protein and mRNA levels in parallel with podocyte apoptosis. Importantly, a time-dependent experiment showed that the occurrence of ERRγ downregulation after PAN challenge was earlier than the onset of cell apoptosis, which further suggested a potential involvement of ERRγ in PAN-induced podocyte apoptosis. To define the role of ERRγ in this pathological process, we silenced ERRγ via an siRNA approach. Interestingly, knockdown of ERRγ alone resulted in a marked podocyte apoptosis. Consistent with the findings from siERRγ experiments, overexpression of ERRγ in podocytes significantly ameliorated PAN-induced cell apoptosis. These findings highly suggested that the downregulation of ERRγ could contribute to PAN-induced podocyte apoptosis at least to some extent. Another phenomenon is that ERRγ silencing led to a significant decrease of podocyte protein nephrin and increase of inflammatory injury markers of B7-1 and cathepsin L (Bao et al., 2015), which provided additional evidence showing the action of ERRγ in opposing the pathological insults. Recently, studies indicated that ERRγ was the key partner of peroxisome proliferator activated receptor (PPAR) γ coactivator-1α (PGC-1α) in regulating mitochondrial oxidative metabolic pathways (Devarakonda et al., 2011). Besides, in endometrial carcinoma tissues, the PGC-1α mRNA was positively correlated with ERRγ expression (Ren et al., 2015). More importantly, adriamycin, a similar inducer of podocyte apoptosis and ERRγ reduction, was reported to decrease PGC-1α in podocytes (Che et al., 2015). These studies indicated that PGC-1α reduction might serve as an upstream mechanism for ERRγ reduction induced by various insults. Thus it is worthwhile to further confirm this possible mechanism mediating ERRγ reduction in current experimental setting in the future.